Structure and dynamics of the interaction of Delta and Omicron BA.1 SARS-CoV-2 variants with REGN10987 Fab reveal mechanism of antibody action

Structure and dynamics of the interaction of Delta and Omicron BA.1 SARS-CoV-2 variants with REGN10987 Fab reveal mechanism of antibody action

Abstract Study of mechanisms by which antibodies recognize different viral strains is necessary for the development of new drugs and vaccines to treat COVID-19 and other infections. Here, we report 2.5 Å cryo-EM structure of the SARS-CoV-2 Delta trimeric S-protein in complex with Fab of the recombin...

Full description

Saved in:
Bibliographic Details
Main Authors: Ekaterina N. Lyukmanova, Evgeny B. Pichkur, Dmitry E. Nolde, Milita V. Kocharovskaya, Valentin A. Manuvera, Dmitriy A. Shirokov, Daria D. Kharlampieva, Ekaterina N. Grafskaia, Julia I. Svetlova, Vassili N. Lazarev, Anna M. Varizhuk, Mikhail P. Kirpichnikov, Zakhar O. Shenkarev
Format: Article
Language:English
Published: Nature Portfolio 2024-12-01
Series:Communications Biology
Online Access:https://doi.org/10.1038/s42003-024-07422-9
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Abstract Study of mechanisms by which antibodies recognize different viral strains is necessary for the development of new drugs and vaccines to treat COVID-19 and other infections. Here, we report 2.5 Å cryo-EM structure of the SARS-CoV-2 Delta trimeric S-protein in complex with Fab of the recombinant analog of REGN10987 neutralizing antibody. S-protein adopts “two RBD-down and one RBD-up” conformation. Fab interacts with RBDs in both conformations, blocking the recognition of angiotensin converting enzyme-2. Three-dimensional variability analysis reveals high mobility of the RBD/Fab regions. Interaction of REGN10987 with Wuhan, Delta, Omicron BA.1, and mutated variants of RBDs is analyzed by microscale thermophoresis, molecular dynamics simulations, and ΔG calculations with umbrella sampling and one-dimensional potential of mean force. Variability in molecular dynamics trajectories results in a large scatter of calculated ΔG values, but Boltzmann weighting provides an acceptable correlation with experiment. REGN10987 evasion of the Omicron variant is found to be due to the additive effect of the N440K and G446S mutations located at the RBD/Fab binding interface with a small effect of Q498R mutation. Our study explains the influence of known-to-date SARS-CoV-2 RBD mutations on REGN10987 recognition and highlights the importance of dynamics data beyond the static structure of the RBD/Fab complex.
ISSN:2399-3642

Similar Items